Human thymus-lymphoid tissue antigen and its presence in leukaemia and lymphoma

An antiserum was prepared by immunizing rabbits with human leukaemic tissue homogenate. Prior to immunization, the rabbits had been made tolerant to normal peripheral leucocytes by repeated injections during the neonatal period to suppress the appearance of antibodies against normal tissue components. When the antiserum was tested by gel diffusion precipitation test, it gave one precipitin line against malignant tissue extracts from most leukaemia and lymphoma cases tested, and against normal thymuses and some spleens and lymph nodes as well. It did not react with tissue extracts prepared from normal non-lymphoid tissus. The antigen responsible for the reaction appeared in foetal thymus at 3 months of gestation and persisted throughout life. It appeared in embryonic spleen after 6 months of gestation and in lymph nodes even later, although in spleen and lymph nodes it was not as invariably demonstrated as in the thymus. Neoplasms of other than lymphoid origin were predominantly negative for the antigen; occasional exceptions were probably due to large amounts of infiltrating lymphoid tissue. Antigen localization was studied by the fluorescent antibody method. The cytoplasm of almost all thymocytes, about 30% spleen cells and 20–40% peripheral lymphocytes was stained. Bone marrow, brain, thyroid, liver and kidney cells were negative. The antigen was partially purified from the soluble fraction of thymus homogenate by ion exchange column chromatography and preparative electrophoresis. Its possible use as a marker for thymus derived normal and neoplastic cells has been discussed.     

A pedigree analysis with minimised ascertainment bias shows anticipation in Met30-transthyretin related familial amyloid polyneuropathy.

In type I familial amyloid polyneuropathy (FAP) caused by a variant Met30-transthyretin (TTR), genetic anticipation has been reported. To determine whether anticipation of the disease is a true biological phenomenon or the result of ascertainment bias, we compared age at onset of the affected child with that of the affected parent in 68 parent-child pairs (including data on assumed age at onset and on asymptomatic obligate heterozygotes and parents at obligate 50% risk) in 15 families. Excluding the parent-child pairs involving the proband and "bilineal pairs", onset occurred earlier in the child than in the transmitting parent in 60 out of 68 "unilineal pairs". After correction for ascertainment bias resulting from incomplete penetrance and reduced biological fitness in early onset patients, the number of anticipation pairs (60 pairs) was still significantly larger than that of non-anticipation pairs (29.7 pairs) (p < 0.05). When the children were sons, the difference in age at onset was significantly greater in the mother-son pairs than in the father-son pairs (p = 0.023). Although not all ascertainment biases could be eliminated, these data show strong evidence that anticipation in the transmission of Met30-TTR FAP is a true biological phenomenon.     

Characterization of psoriasiform and alopecic skin lesions in HLA-B27 transgenic rats.

We have previously reported a multisystem inflammatory disease in transgenic rat lines with high expression of HLA-B*2705 and human beta 2 microglobulin. Skin disease in these rats includes two predominant lesions: 1) marked psoriasiform dermatitis of the tail and digits; and 2) progressive alopecia of face, neck, trunk, and extremities. Here we present the results of a systematic survey of these lesions. Tail and digit skin showed psoriasiform hyperplasia of the epidermis associated with parakeratosis, with marked dermal and epidermal inflammation. The alopecic skin showed perifollicular and follicular mononuclear infiltration and increased numbers of atrophic follicles. Immunohistochemical analysis revealed that B27 expression was prominent on keratinocytes in hyperplastic epidermis where lymphocytic infiltrates were prominent, but was absent in the absence of inflammation. In alopecic lesions, B27 was strongly expressed on follicular epithelium and dermal hair papillae associated with mononuclear infiltrates. T cells, both CD8 and CD4, were most prominent in inflammatory lesions and rat MHC-II expression on keratinocytes, and follicular epithelium was dramatically increased. This study suggests that T cell-mediated immune mechanisms participate in development of cutaneous lesions in HLA-B27 transgenic rats.     

Developmental change of GABA(A) receptor-mediated current in rat hippocampus

Developmental change of GABA(A)ergic inhibitory postsynaptic current in rat hippocampal CA3 region was examined using patch-clamp recording method. Spontaneous and evoked inhibitory postsynaptic currents were recorded from acute hippocampal slices of neonates (postnatal days 2-4) and adults (days 18-38). Decay kinetics of the spontaneous inhibitory postsynaptic current was slower in neonates than in adults. Application of 500 nM zolpidem increased decay time-constants of the inhibitory postsynaptic currents in both groups with a stronger effect on adults. Zinc (50 microM) inhibited the neonatal inhibitory postsynaptic currents but the inhibition was weaker in adults. Modification of the GABA(A)ergic inhibitory postsynaptic currents by furosemide (0.6 mM) or diazepam (100 nM) did not cause marked differences between the neonate and adult groups. These results demonstrate that GABA(A)ergic inhibitory postsynaptic currents in hippocampal CA3 pyramidal cells change developmentally and indicate that different receptor isoforms are functionally expressed between neonates and adults.     

Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice

Mice that lack the p85alpha regulatory subunit of phosphatidylinositol-3 kinase (PI3K) are deficient in gastrointestinal and peritoneal mast cells but have dermal mast cells. Accordingly, these mice show impaired bacterial clearance in response to acute septic peritonitis and are highly susceptible to infection by the intestinal nematode Strongyloides venezuelensis. Systemic anaphylactic shock responses, however, are intact. We found that although reconstitution of PI3Kminus sign/minus sign mice with bone marrow--derived mast cells (BMMCs) restored anti-bacterial immunity, only T helper type 2 (TH2)-conditioned BMMCs, not "standard" BMMCs, were able to restore anti-nematode immunity. This finding highlights the importance of the TH2 response in the control of nematode infection. Thus, PI3K likely plays an essential role in host immune responses by regulating both the development and induction of mast cells.     

Somatic activation of beta-catenin bypasses pre-TCR signaling and TCR selection in thymocyte development

Mutation or ablation of T cell factor 1 and lymphocyte enhancer factor 1 indicated involvement of the Wnt pathway in thymocyte development. The central effector of the Wnt pathway is beta-catenin, which undergoes stabilization upon binding of Wnt ligands to frizzled receptors. We report here that conditional stabilization of beta-catenin in immature thymocytes resulted in the generation of single positive T cells that lacked the alpha beta TCR and developed in the absence of pre-TCR signaling and TCR selection. Although active beta-catenin induced differentiation in the absence of TCRs, its action was associated with reduced proliferation and survival when compared to developmental changes induced by the pre-TCR or the alpha beta TCR.     

Molecular mechanism of a cross-talk between oestrogen and growth factor signalling pathways

Oestrogen (E2) plays significant roles in variety of biological events such as the development and maintenance of female reproductive organs, bone and lipid metabolisms. More recently, from study of knock-out mice deficient in oestrogen receptor (ER) alpha and ERbeta it turned out that normal spermatogenesis requires the E2 actions. Furthermore, this female steroid hormone is also well known to be deeply involved in many pathophysiological events such as osteoporosis and cancer development in female reproductive organs. It is particularly well known that most breast cancer is dependent on E2 in its development. Such E2 actions are thought to be mediated through two subtypes of ERs. Growth factors have been shown to synergize in this E2 signalling pathway, although the actual molecular mechanism largely remains unknown. Recently, we found that the MAP kinase activated by growth factors phosphorylates the Ser118 residue of the human ERalpha A/B domain and this phosphorylation potentiates the N-terminal transactivation function (AF-1) of human ERalpha, indicating the possible molecular mechanism of a novel cross-talk between E2 and growth factor signalling pathways. More recently, we have identified a coactivator associating with the hERalpha AF-1 in a MAPK-mediated phosphorylation-dependent manner. In this review, the molecular mechanism of this cross-talk is discussed in terms of the transactivation function of ERs, and their coactivators.     

Inhibition of the slow inward current and the time-dependent outward current of mammalian ventricular muscle by gentamicin

The aminoglycoside antibiotic, gentamicin (GM), depressed the plateau phase and shortened the duration of the action potential in guinea pig papillary muscle. Its effect on the membrane currents was studied by a single sucrose gap voltage clamp method. The slow inward current (i_s) was remarkably diminished by GM with little change in its time course, in the voltage-dependency of the steady-state inactivation and activation or in its reversal potential. The maximal amplitude of i_s, obtained by subtracting the Co²⁺-resistant current, was reduced to 57% by 0.1 mmol/l GM and almost reduced to zero by 1 mmol/l GM. The efficacy of GM in inhibiting i_s was reduced by increasing the external Ca²⁺ concentration from 1.8 to 5.4 or 10.8 mmol/l, but not by the application of adrenaline. The time-dependent outward current (i_K) was also decreased by GM but only at higher concentrations. It is proposed that the depressant action of GM on i_s was due to a blockade of slow channels, whereby GM may have dislocated Ca from the binding sites at slow channels on the external surface of the membrane.